Formulations and Methods of Treating Inflammatory Bowel Disease

ABSTRACT

Methods and formulations for treating inflammatory bowel disease are disclosed. The methods and formulations include, but are not limited to, methods and formulations for delivering effective concentrations of 4-aminosalicylic acid and/or 5-aminosalicylic acid to affected areas of the intestine. The methods and formulations comprise modified-release elements, providing for drug delivery to the affected or desired area. Diseases and conditions treatable with the present invention include Crohn&#39;s disease and ulcerative colitis.

This application claims the benefit of priority of U.S. ProvisionalPatent Application No. 60/499,365 filed Sep. 3, 2003, which isincorporated herein by reference in its entirety.

This invention is directed to methods and formulations for treatinginflammatory bowel disease. The methods and formulations include, butare not limited to, methods and formulations for delivering effectiveconcentrations of 4-aminosalicylic acid and/or 5-aminosalicylic acid toaffected areas of the intestine. The methods and formulations cancomprise conventional and/or modified-release elements, providing fordrug delivery to the affected area. Diseases and conditions treatablewith the methods and formulations of the present invention includeCrohn's disease and ulcerative colitis.

Gastrointestinal conditions pose a significant worldwide health problem.Inflammatory bowel diseases, which genus encompass a range of diseasesincluding Crohn's disease and ulcerative colitis, affect nearly 1million people in the United States each year.

The two most common inflammatory conditions of the intestine, ulcerativecolitis (UC) and Crohn's disease (CD), are collectively known asinflammatory bowel disease (IBD). These conditions are diseases of thedistal gut (lower small intestine, large intestine, and rectum) ratherthan the proximal gut (stomach and upper small intestine). Between thetwo, ulcerative colitis primarily affects the colon, whereas Crohn'sdisease affects the distal small intestine as well.

Although distinct conditions, the same drugs are commonly used to treatboth UC and CD. Drugs commonly used in their treatment include steroids(for example, budesonide and other corticosteroids, and adrenal steroidssuch as prednisone and hydrocortisone), cytokines such asinterleukin-10, antibiotics, immunomodulating agents such asazathioprine, 6-mercaptopurine, methotrexate, cyclosporine, andanti-tumor necrosis factor (TNF) agents such as soluble TNF receptor andantibodies raised to TNF, and also antinflammatory agents such as zinc.The most commonly prescribed agents for IBD include sulfasalazine(salicyl-azo-sulfapyridine, or “SASP”) and related 5-aminosalicylic acid(“5-ASA”) products.

It is recognized that SASP is broken down in the lower gut by colonicbacteria to yield sulfapyridine (“SP”) and 5-ASA, of which 5-ASA isbelieved to be the primary active component. 5-ASA released in the colonis poorly absorbed and appears to act locally.

Because SP is extensively absorbed and is associated with various sideeffects, investigators have proposed using 5-ASA alone as a treatmentfor IBD. Indeed, 5-ASA, or mesalamine, has now been established as acommon treatment for IBD and is widely prescribed and used for thispurpose. However, 5-ASA therapy still has problems, including sideeffects to be detailed hereinafter. Additionally, 5-ASA exhibits anefficacy profile that is less than maximal, reflected in lower responseand remission rates, and higher relapse rates, related to its site andmechanism of action.

The administration of 5-ASA is hampered by some complications associatedwith its delivery. For example, the compound is unstable in gastricfluids, and its extensive absorption and metabolism from the smallintestine reduces its availability at distal sites in the gut, which arethe sites of the therapeutic effect and the preferred sites of delivery.Ideally, the compound should reach the distal gut, but not be absorbedthere. The absorption from proximal sites results in side effectsassociated with the absorbed drug and its systemic effects.

Existing oral 5-ASA-based therapies fall into two main categories. Oneinvolves the use of pharmaceutical dosage forms based onmodified-release formulations (MR), the other is pro-drug based. Inrelation to dosage form-based approaches, various modified release formshave been developed and described. Both extended/sustained releaseformulations and delayed release formulations have been developed, withthe intent of limiting 5-ASA release in the upper gut and concentratingits release in the distal gut.

For example, a sustained release formulation (PENTASA®) has beenapproved and used for many years. PENTASA® releases 5-ASA continuously,with approximately 50% released in the small intestine and 50% in thelarge intestine, and in its approved label form reports 20-30% systemicabsorption. This absorption reflects the proximal release and absorptioncharacteristics of this formulation in addition to any low levelabsorption from the distal gut. (See PDR datasheet for PENTASA®.) U.S.Pat. Nos. 4,496,553, 4,880,794, 4,980,173, and 5,041,431 are alldirected to extended release forms of 5-ASA or its salts or esters.

U.S. Pat. No. 5,840,332 describes a GI delivery system that achieves thedesired location of release of 5-ASA in the intestine through theinclusion of particulate water-insoluble material embedded in awater-insoluble coating on a drug-containing core. U.S. Pat. No.6,004,581 describes a multiparticulate spherical-granule-containingformulation that provides for a modified and targeted release of 5-ASA,particularly to the small and large bowel. In all of these cases,however, the fundamental problems of proximal release limiting themaximum local efficacy, and resulting in significant side effectsrelated to the systemic absorption of 5-ASA, have not been overcome.

Other approaches rely on a pH-dependent coating to achieve the desiredrelease. For example, an enteric-coated commercial product, ASACOL®,relies on a pH-dependent acrylic-based barrier coating, which dissolvesat pH values above 7, to achieve a distal 5-ASA delivery. Other examplesof this type of formulation are described in U.S. Pat. Nos. 5,541,170and 5,541,171, which describe a solid dosage form of 5-ASA, or its saltsor esters, that achieves delivery to the large intestine through acoating that is insoluble in gastric and intestinal conditions (lessthan pH 7) but soluble in the colon (pH greater than 7).

The drawback of formulations such as these is that the regional gut pHcan vary significantly from one person to the next, and can beinfluenced by the presence of food, or other conditions. In fact,diseases such as IBD can themselves cause intestinal pH to vary. Thepackage information for ASACOL® states that its systemic absorption isas high as 28%. Because absorption is generally occurring only in thesmall intestine, the relatively high systemic absorption suggests asignificant variability in ASACOL®'s site of release.

In general, pH-dependent systems for targeting 5-ASA release to aspecific location in the intestine can be unreliable for a number ofreasons. For example, premature release and associated systemicabsorption may result from a proximal intestinal pH at or above thecritical triggering pH. Alternatively, incomplete or minimal release mayresult from the occurrence of the critical pH at a site distal of theaffected area. Nugent et al., Gut 48, pages 571-577 (2001), reviews thepotential problems of the pH-dependent distal gut delivery approach,pointing out that the existence of inter-subject variations inintestinal pH. These problems have led to proposed improvements intargeting the delivery of 5-ASA to the distal gut.

U.S. Pat. No. 5,716,648 describes an oral composition that relies on apH-dependent soluble coating, but also includes a pH-regulating alkalinematerial to attempt to compensate for patients with “subnormalintestinal pH.” Other approaches include those described in U.S. Pat.No. 5,866,619, which is generally directed to a non-pH-dependent colonicdrug-delivery system involving a saccharide-containing polymer, which isenzymatically degraded by the colon. Another example is provided by U.S.Pat. No. 6,506,407, which generally describes a colon-specificdrug-releasing system that combines a pH-dependent outer coating withthe inclusion of a saccharide substrate, which upon enzymatic breakdownby enterobacteria produces an organic acid that subsequently dissolvesan acid-soluble inner coating.

Still other examples are described in U.S. Application No. 2002/0098235,which describes the use of multiple pH-dependent coatings to reduce theimpact of coating fractures. U.S. Application No. 2001/0055616 describesa pellet formulation for treating intestinal tract conditions, whichutilizes a pH-dependent enteric coating to target release from anon-gel-forming drug-containing polymeric matrix core. U.S. Application2001/0036473 describes a pH-dependent coating on ahydroxypropylmethylcellulose capsule for enteric and colonic delivery.And U.S. Application No. 2001/0026807 describes various coatings,including pH-dependent materials, redox-sensitive materials, andmaterials subject to breakdown by bacteria, on a starch capsule toachieve colonic delivery.

Despite the descriptions of proposed improvements in these documents, acolonic 5-ASA-delivery system that does not suffer from the variabilityin inter-subject intestinal pH is still not commercially available.Thus, the inherent difficulties in 5-ASA delivery have yet to be solvedin a commercially acceptable manner.

A compound related to, but more stable than 5-ASA, is 4-ASA, also knownas para-aminosalicylic acid. Like 5-ASA, 4-ASA is effective in treatingIBD, although it has never been approved in oral form for such a use. Ithas been approved for use in certain European countries as a rectalenema, i.e., QUADRAS® by Norgine.

4-ASA has been used as an oral preparation since the 1940s as atreatment for tuberculosis (TB). Para-aminosalicylic acid has certainadvantages over 5-ASA in treating IBD. In addition to its higher aqueousstability, it reportedly exhibits an absence of nephrotoxicity, andextensive experience and use at daily doses as high as 8 g in thetreatment of TB has demonstrated its safety. (Ginsberg et al.,Gastroenterology 102, 448-452, 1998.)

As an approved form for use in TB, 4-ASA is commonly presented as anenteric formulation in order to minimize the degradation of the drug inthe stomach. Modified release oral dosage forms of 4-ASA for use in TBhave also been described. Because absorption of the 4-ASA is importantin TB treatment, such formulations are designed to maximize 4-ASAabsorption.

Unlike the situation with 5-ASA, modified-release oral dosage forms of4-ASA for use in IBD have not been widely described. U.S. Pat. No.5,716,648 does describe an oral composition for 4-ASA in treating IBD.However, this disclosure is directed specifically to pharmaceutical oralcompositions that include a pH regulating alkaline material to deal withsubnormal gut pH.

In addition to targeting IBD with modified-release 5-ASA products, IBDhas been targeted with pro-drugs that are self-targeting. For example,olsalazine, which is formed from two molecules of 5-ASA linked by anazo-bond (5,5′-azo-bis salicylic acid), naturally targets the colon. Itis stable in gastric conditions, thus able to bypass the stomach, and isminimally absorbed intact from the gut (2.4%). But it is rapidlyconverted to two molecules of 5-ASA in the colon through the action ofcolonic bacteria. This mechanism inherently delivers 5-ASA to thedesired site of action. The marketed form of olsalazine, DIPENTUM®, is asimple non-modified-release powder-filled capsule.

The problem with this formulation is that the entire dose is exposed tothe action of the intestinal enzymes upon entering the colon. Thus, uponentering the colon, all of the olsalazine is cleaved into 5-ASA,essentially providing a bolus dose to a concentrated area in theproximal colon. After a fairly substantial absorption (approximately20%), the remainder of the bolus dose is then left to diffuse throughoutthe colon, without any control as to where it is directed.

Because olsalazine is self-targeting to the colon, there has been littlefocus on modified release forms of olsalazine or other bis-azo ASApro-drug forms. U.S. Patent Application No. 2002/0192282 describes amultilayer pharmaceutical formulation for release of various drugs,including olsalazine, in the colon and includes a pH-dependent outercoating layer. The problem with such a formulation was described abovewith respect to other pH-dependent formulations: because of thepotential variability in the pH of the gut, these systems may notproperly release at affected sites due to distal gut pH values below thecritical value.

U.S. Pat. No. 4,374,932 describes a drug delivery system for5,5′-azo-bis salicylic acid designed to bypass absorption of the5,5′-azo-bis salicylic acid entity in the stomach and small intestine,and utilizes an ion-exchange complex of diacidic 5,5′-azo-bis salicylicacid and an anionic exchange resin. However, the absorption ofolsalazine from the conventional powder capsule already results in only2.4% absorption, and thus this formulation does not provide an importanttherapeutic advantage.

In view of the foregoing, there remains a need in the art for methodsand pharmaceutical formulations that can be used to deliver 4-ASA and/or5-ASA in therapeutically effective concentrations to affected areas ofthe gastrointestinal tract. The present invention solves the problemsidentified in the art, and provides such methods and formulations.

This invention is advantageous in providing methods and formulations fortreating inflammatory bowel disease.

The invention has the advantage of delivering effective concentrationsof 4-ASA and/or 5-ASA to affected areas of the gastrointestinal tract,with minimized systemic absorption.

The invention is directed to, among other things, disodium 4,4′-azo-bissalicylate. The invention is also directed to pharmaceuticalcompositions comprising 4,4′-azo-bis salicylic acid, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient. In some embodiments, thepharmaceutically acceptable salt thereof comprises disodium4,4′-azo-bis-salicylate. In some embodiments, the pharmaceuticallyacceptable excipient is chosen from carriers, fillers, extenders,binders, humectants, disintegrating agents, solution-retarding agents,absorption accelerators, wetting agents, absorbents, lubricants,stabilizers, coloring agents, buffering agents, dispersing agents,preservatives, organic acids, and organic bases.

The invention is also directed to pharmaceutical compositionscomprising: a salicylate and/or salicylic acid chosen from 4-aminosalicylic acid, 5-amino salicylic acid, pharmaceutically acceptablesalts thereof, and pro-drugs thereof, and at least one pharmaceuticallyacceptable excipient, formulated as a modified-release pharmaceuticalcomposition, wherein the composition exhibits a delay in release that isdependent on surrounding pH.

The pharmaceutical composition may exhibit the following dissolutionprofile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C.and 50 rpm, in 0.01 N HCl for two hours followed by pH 6.8 buffer forthe remainder of the test: 1 hour (in 0.01 N HCl): from about 0 to about10% drug released; 2 hours (in 0.01 N HCl): from about 0 to about 10%drug released; 1 hour (in pH 6.8): from about 10 to about 35% drugreleased; 2 hours (in pH 6.8): from about 20 to about 65% drug released;4 hours (in pH 6.8): from about 55 to about 95% drug released; 6 hours(in pH 6.8): from about 90 to about 100% drug released; and 12 hours (inpH 6.8): about 90% or greater drug released. In some embodiments, thecomposition exhibits the following dissolution profile, when tested in aU.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in 0.01N HClfor two hours followed by pH 6.8 buffer for the remainder of the test: 1hour (in 0.01 N HCl): from about 0 to about 5% drug released; 2 hours(in 0.01 N HCl): from about 0 to about 5% drug released; 1 hour (in pH6.8): from about 15 to about 30% drug released; 2 hours (in pH 6.8):from about 25 to about 60% drug released; 4 hours (in pH 6.8): fromabout 60 to about 90% drug released; 6 hours (in pH 6.8): from about 90to about 100% drug released; and 12 hours (in pH 6.8): about 95% orgreater drug released.

The present invention is also directed to pharmaceutical compositionscomprising: a salicylate and/or salicylic acid chosen from 4-aminosalicylic acid, 5-amino salicylic acid, pharmaceutically acceptablesalts thereof, and pro-drugs thereof, and at least one pharmaceuticallyacceptable excipient, formulated as a modified-release pharmaceuticalcomposition, wherein the composition exhibits a drug-release profilethat is independent of surrounding pH.

The composition may exhibit the following dissolution profile, whentested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, inpH 6.8 buffer for the test: 1 hour: less than or equal to about 10% drugreleased; 2 hours: from about 0 to about 35% drug released; 3 hours:from about 10 to about 60% drug released; 4 hours: from about 20 toabout 60% drug released; 6 hours: from about 40 to about 80% drugreleased; and 12 hours: from about 75 to about 100% drug released. Insome embodiments, the composition exhibits the following dissolutionprofile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C.and 50 rpm, in pH 6.8 buffer for the test: 1 hour: less than or equal toabout 5% drug released; 2 hours: from about 0 to about 25% drugreleased; 3 hours: from about 15 to about 30% drug released; 4 hours:from about 40 to about 50% drug released; 6 hours: from about 60 toabout 75% drug released; and 12 hours: from about 90 to about 100% drugreleased.

The modified-release compositions of the invention may comprise animmediate-release core and a semi-permeable membrane. In someembodiments, the modified-release compositions of the invention maycomprise a modified-release matrix core and a semi-permeable membrane.In some embodiments, the salicylate and/or salicylic acid is chosen from4-aminosalicylic acid and 5-aminosalicylic acid, or at least onepharmaceutically acceptable salt or ester thereof. In some embodiments,the composition comprises 4-aminosalicylic acid and 5-aminosalicylicacid, or pharmaceutically acceptable salts or esters thereof. In someembodiments, the salicylate and/or salicylic acid is chosen from5,5′-azo-bis salicylic acid, 4,5′-azo-bis salicylic acid, 4,4′-azo-bissalicylic acid, and pharmaceutically acceptable salts thereof.

The invention also includes methods of treating inflammatory boweldisease comprising administering an effective amount of 4,4′-azo-bissalicylic acid to a subject in need of such treatment. The method mayinclude administering 4,4′-azo-bis salicylic acid in a modified-releaseformulation. In some embodiments, the modified-release formulationexhibits a release profile with delayed-release and extended-releaseproperties.

The foregoing and other objects, features, and advantages of theinvention will be apparent from the following more particulardescription of various embodiments of the invention. It is to beunderstood that both the foregoing general description and the followingmore detailed description are exemplary and explanatory only and are notrestrictive of the invention, as claimed.

This invention relates to formulations and methods for treatinginflammatory bowel disease. The term “inflammatory bowel disease”includes, but is not limited to, ulcerative colitis and Crohn's disease.Other diseases contemplated for treatment or prevention by the presentinvention include non-ulcerative colitis, and carcinomas, polyps, and/orcysts of the colon and/or rectum. All of these diseases fall within thescope of the term “inflammatory bowel disease” as used in thisspecification, yet the invention does not require the inclusion of eachrecited member. Thus, for example, the invention may be directed to thetreatment of Crohn's disease, to the exclusion of all the other members;or to ulcerative colitis, to the exclusion of all the other members; orto any single disease or condition, or combination of diseases orconditions, to the exclusion of any other single disease or condition,or combination of diseases or conditions.

The inventive formulations and methods provide for the delivery ofeffective concentrations of 4-ASA and/or 5-ASA to the desired oraffected area, e.g., the distal small intestine and/or colon, of theintestinal tract. The invention includes modified-release formulationsof 4-ASA and/or 5-ASA, including formulations that exhibit delayed-and/or extended-release characteristics.

In other embodiments, formulations include a “pro-drug” of 4-ASA and/or5-ASA. As used herein, the term “pro-drug” means any compound orcomposition that yields an active agent at some point followingadministration. Thus, for example, a pro-drug of 4-ASA is one thatyields 4-ASA; a pro-drug of 5-ASA, or a 5-ASA pro-drug, is one thatyields 5-ASA. There is no requirement that the pro-drug itself beinactive—in some instances the pro-drug can be active, and yet stillyield a different active agent. There is also no requirement that apro-drug yield only one active agent—a pro-drug may yield two or moreactive agents, and the yielded agents may be the same or different.Examples of pro-drugs useful in accordance with this invention include,but are not limited to, sulfasalazine, which yields 5-ASA in the colon,and olsalazine, which comprises two molecules of 5-ASA linked by anazo-bond, i.e., 5,5′-azo-bis-salicylic acid, and yields two molecules of5-ASA.

Olsalazine, as discussed above, has the advantage of being stable ingastric conditions and being minimally absorbed intact from the gut(2.4%). Olsalazine is rapidly converted to two molecules of 5-ASA in thecolon through the action of colonic bacteria. This is the same mechanismby which 5-ASA is formed from sulfasalazine in the colon.

The modified-release formulations of the current invention are directedto modifying the release of, for example, olsalazine so that thecleavage of 5-ASA from olsalazine occurs at a slow and controlledmanner. The advantage of this new approach is that it reduces the rapidand extensive conversion of olsalazine to 5-ASA by the action of thecolonic bacteria and the low prevailing redox potential. WhereasDIPENTUM® (commercially available form of olsalazine) results in a highlocal concentration of 5-ASA in the distal gut, resulting in systemicabsorption of 5-ASA or its acetylated form (approximately 20%), themodified-release formulations of the current invention, by regulatingthe rate at which the pro-drug is made available for conversion andthereby for formation of the active moiety, overcome these problems andprovide for a safer and more effective form.

In addition to olsalazine, the present invention is also directed to theuse of 4,5′-azo-bis salicylic acid, described in U.S. Pat. No.4,591,584, which is converted in the distal gut to both 4-ASA and 5-ASA.Also included within the scope of this invention is 4,4′-azo-bissalicylic acid, which has not been described previously as an agent fortreating IBD. This form will be converted exclusively to 4-ASA and canbe administered in both un-modified and modified-release forms.Modified-release formulations of 5,5′ azo-bis, 5,4′ azo-bis, 4,4′azo-bis, and combinations thereof, are also within the scope of thisinvention. In fact, the inventors expressly contemplate the use of anypro-drugs that yield 4-ASA and/or 5-ASA.

In this regard, reference is made to U.S. Pat. No. 6,602,915, directedto therapeutic azo-compounds for drug delivery. This patent is generallydirected to polymers of azo-compounds, including polymers of azo-linked4-ASA and polymers of azo-linked 5-ASA. The use of such polymers, andformulations containing them, is within the scope of the presentinvention.

Balsalazide is a commercially available pro-drug of 5-ASA that iscleaved in the colon to release 5-ASA together with a largely unabsorbedand inert moiety, 4-aminobenzoyl-beta-alanine. U.S. Pat. No. 6,458,776describes a derivative of 5-ASA that, upon reduction of the azo bond inthe colon, releases both 5-ASA and a non-absorbable antibiotic. Thesepro-drug compounds are also within the scope of the present invention,and can be formulated as modified-release formulations according to theinvention.

Indeed, the present invention is not limited to any of the particularazo-bis compounds described herein. The present invention extends to theuse and formulation of any azo-bis compound that yields either 4-ASAand/or 5-ASA. Modified-release formulations of any such azo-bis compoundare specifically contemplated. Thus, as used herein in association withthe present invention, the term “drug” refers to compounds useful intreating IBD or other diseases according to this invention, includingbut not limited to SASP, 5-ASA, and/or 4-ASA; the term “pro-drug” refersto any compound that yields such drugs, including but not limited toolsalazine, balzalazine, and/or any other azo-containing compound thatyields such drug or drugs.

As used herein, the term “modified-release” formulation or dosage formincludes pharmaceutical preparations that achieve a desired release ofthe drug from the formulation. A modified-release formulation can bedesigned to modify the manner in which the active ingredient is exposedto the desired target. For example, a modified-release formulation canbe designed to focus the delivery of the active agent entirely in thedistal large intestine, beginning at the cecum, and continuing throughthe ascending, transverse, and descending colon, and ending in thesigmoid colon. Alternatively, for example, a modified-releasecomposition can be designed to release to focus the delivery of the drugin the proximal small intestine, beginning at the duodenum and ending atthe ileum. In still other examples, the modified-release formulationscan be designed to begin releasing active agent in the jejunum and endtheir release in the transverse colon. The possibilities andcombinations are numerous, and are clearly not limited to theseexamples.

The term “modified-release” encompasses “extended-release” and“delayed-release” formulations, as well as formulations having bothextended-release and delayed-release characteristics. An“extended-release” formulation can extend the period over which drug isreleased or targeted to the desired site. A “delayed-release”formulation can be designed to delay the release of the pharmaceuticallyactive compound for a specified period. Such formulations are referredto herein as “delayed-release” or “delayed-onset” formulations or dosageforms. Modified-release formulations of the present invention includethose that exhibit both a delayed- and extended-release, e.g.,formulations that only begin releasing after a fixed period of time orafter a physicochemical change has occurred, for example, then continuereleasing over an extended period.

As used herein, the term “immediate-release formulation,” is meant todescribe those formulations in which more than about 50% of activeingredient is released from the dosage form in less than about 2 hours.Such formulations are also referred to herein as “conventionalformulations.”

The formulations of the present invention are intended to includeformulations that are generic to treating all forms of IBD, and thustarget their contents to both the distal small intestine and the largeintestine. Other formulations within the scope of the invention includethose that are more specifically designed for treating a specificdisease. For example, a formulation for treating ulcerative colitis canbe designed to deliver its contents entirely to the colon.

The formulations of the present invention can exist as multi-unit orsingle-unit formulations. The term “multi-unit” as used herein means aplurality of discrete or aggregated particles, beads, pellets, granules,tablets, or mixtures thereof, for example, without regard to their size,shape, or morphology. Single-unit formulations include, for example,tablets, caplets, and pills.

The methods and formulations of the present invention are intended toencompass all possible combinations of components that exhibitmodified-release and immediate-release properties. For example, aformulation and/or method of the invention can contain components thatexhibit extended-release and immediate-release properties, or bothdelayed-release and immediate-release properties, or bothextended-release and delayed-release properties, or a combination of allthree properties. For example, a multiparticulate formulation includingboth immediate-release and extended-release components can be combinedin a capsule, which is then coated with an enteric coat to provide adelayed-release effect. Or, for example, a delayed- and extended-releasecaplet may comprise a plurality of discrete extended-release particlesheld together with a binder in the caplet, which is coated with anenteric coating to create a delay in dissolution.

The modifications in the rates of release, such as to create a delay orextension in release, can be achieved in any number of ways. Mechanismscan be dependent or independent of local pH in the intestine, and canalso rely on local enzymatic activity to achieve the desired effect.Examples of modified-release formulations are known in the art and aredescribed, for example, in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566.

A number of modified dosage forms suitable for use are described below.A more detailed discussion of such forms can also be found in, forexample The Handbook of Pharmaceutical Controlled Release Technology, D.L. Wise (ed.), Marcel Decker, Inc., New York (2000); and also inTreatise on Controlled Drug Delivery: Fundamentals, Optimization, andApplications, A. Kydonieus (ed.), Marcel Decker, Inc., New York, (1992),the relevant contents of each of which are hereby incorporated byreference for this purpose. Examples of modified-release formulationsinclude but are not limited to, membrane-modified, matrix, osmotic, andion-exchange systems. All of these can be in the form of single-unit ormulti-unit dosage forms, as alluded to above.

With membrane-modified extended-release dosage forms, a semi-permeablemembrane can surround the formulation containing the active substance ofinterest. Semi-permeable membranes include those that are permeable to agreater or lesser extent to both water and solute. This membrane caninclude water-insoluble and/or water-soluble polymers, and can exhibitpH-dependent and/or pH-independent solubility characteristics. Polymersof these types are described in detail below. Generally, thecharacteristics of the polymeric membrane, which may be determined by,e.g., the composition of the membrane, will determine the nature ofrelease from the dosage form.

Matrix-Based Dosage Forms

Matrix-type systems comprise an active substance of interest, mixed witheither water-soluble, e.g., hydrophilic polymers, or water-insoluble,e.g., hydrophobic polymers. Generally, the properties of the polymerused in a modified-release dosage form will affect the mechanism ofrelease. For example, the release of the active ingredient from a dosageform containing a hydrophilic polymer can proceed via both surfacediffusion and/or erosion. Mechanisms of release from pharmaceuticalsystems are well known to those skilled in the art. Matrix-type systemscan also be monolithic or multiunit, and can be coated withwater-soluble and/or water-insoluble polymeric membranes, examples whichare described above.

Matrix formulations of the present invention can be prepared by using,for example, direct compression or wet granulation. A functionalcoating, as noted above, can then be applied in accordance with theinvention. Additionally, a barrier or sealant coat can be applied over amatrix tablet core prior to application of a functional coating. Thebarrier or sealant coat can serve the purpose of separating an activeingredient from a functional coating, which can interact with the activeingredient, or it can prevent moisture from contacting the activeingredient. Details of barriers and sealants are provided below.

In a matrix-based dosage form in accordance with the present invention,the drug and/or pro-drug and optional pharmaceutically acceptableexcipient(s) are dispersed within a polymeric matrix, which typicallycomprises one or more water-soluble polymers and/or one or morewater-insoluble polymers. The drug can be released from the dosage formby diffusion and/or erosion. Wise and Kydonieus describe such matrixsystems in detail.

Suitable water-soluble polymers include, but are not limited to,polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, or polyethyleneglycol, and/or mixtures thereof.

Suitable water-insoluble polymers also include, but are not limited to,ethylcellulose, cellulose acetate, cellulose propionate, celluloseacetate propionate, cellulose acetate butyrate, cellulose acetatephthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethylmethacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate),and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly(lauryl methacrylate), poly (phenyl methacrylate), poly (methylacrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly(octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly(ethylene) high density, poly (ethylene oxide), poly (ethyleneterephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly(vinyl chloride) or polyurethane, and/or mixtures thereof.

Suitable pharmaceutically acceptable excipients include, but are notlimited to, carriers, such as sodium citrate and dicalcium phosphate;fillers or extenders, such as stearates, silicas, gypsum, starches,lactose, sucrose, glucose, mannitol, talc, and silicic acid; binders,such as hydroxypropyl methylcellulose, hydroxymethyl-cellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia;humectants, such as glycerol; disintegrating agents, such as agar,calcium carbonate, potato and tapioca starch, alginic acid, certainsilicates, EXPLOTAB™, crospovidone, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as cetyl alcohol andglycerol monostearate; absorbents, such as kaolin and bentonite clay;lubricants, such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, and sodium lauryl sulfate; stabilizers, such asfumaric acid; coloring agents; buffering agents; dispersing agents;preservatives; organic acids; and organic bases. The aforementionedexcipients are given as examples only and are not meant to include allpossible choices. Additionally, many excipients can have more than onerole or function, or can be classified in more than one group; theclassifications are descriptive only, and are not intended to limit anyuse of a particular excipient.

In one example, a matrix-based dosage form can comprise the drug orpro-drug, a filler, such as starch, lactose, or microcrystallinecellulose (AVICEL™); a binder/controlled-release polymer, such ashydroxypropyl methylcellulose or polyvinyl pyrrolidone; a disintegrant,such as EXPLOTAB™, crospovidone, or starch; a lubricant, such asmagnesium stearate or stearic acid; a surfactant, such as sodium laurylsulfate or polysorbates; and a glidant, such as colloidal silicondioxide (AEROSIL™) or talc.

The amounts and types of polymers, and the ratio of water-solublepolymers to water-insoluble polymers in the inventive formulations aregenerally selected to achieve a desired release profile of the drug orpro-drug, as described below. For example, by increasing the amount ofwater insoluble-polymer relative to the amount of water soluble-polymer,the release of the drug can be delayed or slowed. This is due, in part,to an increased impermeability of the polymeric matrix, and, in somecases, to a decreased rate of erosion during transit through thegastrointestinal tract.

Of course, matrix-based dosage forms may be coated with adiffusion-control membrane, such as a semi-permeable or selectivelypermeable membrane. Indeed, many of the formulation components describedherein can be used in combination: instant release cores withdiffusion-controlled membranes or matrix cores with diffusion-controlledmembranes, for example.

Osmotic Pump Dosage Forms

In another embodiment, the modified-release formulations of the presentinvention are provided as osmotic pump dosage forms. In an osmotic pumpdosage form, a core containing drug or pro-drug and optionally one ormore osmotic excipients is typically encased by a selectively permeablemembrane having at least one orifice. The selectively permeable membraneis generally permeable to water, but impermeable to the drug. When thesystem is exposed to body fluids, water penetrates through theselectively permeable membrane into the core containing the drug andoptional osmotic excipients. The osmotic pressure increases within thedosage form. Consequently, the drug is released through the orifice(s)in an attempt to equalize the osmotic pressure across the selectivelypermeable membrane.

In more complex pumps, the dosage form can contain two internalcompartments in the core. The first compartment contains the drug andthe second compartment can contain a polymer, which swells on contactwith aqueous fluid. After ingestion, this polymer swells into thedrug-containing compartment, diminishing the volume occupied by thedrug, thereby forcing the drug from the device at a controlled rate overan extended period of time. Such dosage forms are often used when a zeroorder release profile is desired.

Osmotic pumps are well known in the art. For example, U.S. Pat. Nos.4,088,864, 4,200,098, and 5,573,776, each of which is herebyincorporated by reference for this purpose, describe osmotic pumps andmethods of their manufacture. Osmotic pumps of the present invention canbe formed by compressing a tablet of an osmotically active drug, or anosmotically inactive drug in combination with an osmotically activeagent, and then coating the tablet with a selectively permeable membranewhich is permeable to an exterior aqueous-based fluid but impermeable tothe drug and/or osmotic agent.

One or more delivery orifices can be drilled through the selectivelypermeable membrane wall. Alternatively, one or more orifices in the wallcan be formed by incorporating leachable pore-forming materials in thewall. In operation, the exterior aqueous-based fluid is imbibed throughthe selectively permeable membrane wall and contacts the drug to form asolution or suspension of the drug. The drug solution or suspension isthen pumped out through the orifice, as fresh fluid is imbibed throughthe selectively permeable membrane.

Typical materials for the selectively permeable membrane includeselectively permeable polymers known in the art to be useful in osmosisand reverse osmosis membranes, such as cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, agar acetate, amylose triacetate, beta glucanacetate, acetaldehyde dimethyl acetate, cellulose acetate ethylcarbamate, polyamides, polyurethanes, sulfonated polystyrenes, celluloseacetate phthalate, cellulose acetate methyl carbamate, cellulose acetatesuccinate, cellulose acetate dimethyl aminoacetate, cellulose acetateethyl carbamate, cellulose acetate chloracetate, cellulose dipalmitate,cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanate,cellulose acetate valerate, cellulose acetate succinate, cellulosepropionate succinate, methyl cellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, lightly cross-linked polystyrenederivatives, cross-linked poly(sodium styrene sulfonate),poly(vinylbenzyltrimethyl ammonium chloride), cellulose acetate,cellulose diacetate, cellulose triacetate, and/or mixtures thereof.

The osmotic agents that can be used in the pump are typically soluble inthe fluid that enters the device following administration, resulting inan osmotic pressure gradient across the selectively permeable wallagainst the exterior fluid. Suitable osmotic agents include, but are notlimited to, magnesium sulfate, calcium sulfate, magnesium chloride,sodium chloride, lithium chloride, potassium sulfate, sodium carbonate,sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate,D-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose,hydrophilic polymers such as cellulose polymers, and/or mixturesthereof.

As discussed above, the osmotic pump dosage form can contain a secondcompartment containing a swellable polymer. Suitable swellable polymerstypically interact with water and/or aqueous biological fluids, whichcauses them to swell or expand to an equilibrium state. Acceptablepolymers exhibit the ability to swell in water and/or aqueous biologicalfluids, retaining a significant portion of such imbibed fluids withintheir polymeric structure, so as to increase the hydrostatic pressurewithin the dosage form. The polymers can swell or expand to a very highdegree, usually exhibiting a 2- to 50-fold volume increase. The polymerscan be non-cross-linked or cross-linked. In one embodiment, theswellable polymers are hydrophilic polymers.

Suitable polymers include, but are not limited to, poly (hydroxy alkylmethacrylate) having a molecular weight of from 30,000 to 5,000,000;kappa-carrageenan; polyvinylpyrrolidone having a molecular weight offrom 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolytecomplexes; poly (vinyl alcohol) having low amounts of acetate,cross-linked with glyoxal, formaldehyde, or glutaraldehyde, and having adegree of polymerization from 200 to 30,000; a mixture including methylcellulose, cross-linked agar and carboxymethyl cellulose; awater-insoluble, water-swellable copolymer produced by forming adispersion of finely divided maleic anhydride with styrene, ethylene,propylene, butylene or isobutylene; water-swellable polymers of N-vinyllactams; and/or mixtures of any of the foregoing.

The term “orifice” as used herein comprises means and methods suitablefor releasing the drug from the dosage form. The expression includes oneor more apertures or orifices that have been bored through theselectively permeable membrane by mechanical procedures. Alternatively,an orifice can be formed by incorporating an erodible element, such as agelatin plug, in the selectively permeable membrane. In such cases, thepores of the selectively permeable membrane form a “passageway” for thepassage of the drug. Such “passageway” formulations are described, forexample, in U.S. Pat. Nos. 3,845,770 and 3,916,899, the relevantdisclosures of which are incorporated herein by reference for thispurpose.

The osmotic pumps useful in accordance with this invention can bemanufactured by known techniques. For example, the drug and otheringredients can be milled together and pressed into a solid having thedesired dimensions (e.g., corresponding to the first compartment). Theswellable polymer is then formed, placed in contact with the drug, andboth are surrounded with the selectively permeable agent. If desired,the drug component and polymer component can be pressed together beforeapplying the selectively permeable membrane. The selectively permeablemembrane can be applied by any suitable method, for example, by molding,spraying, or dipping.

Membrane-Modified Dosage Forms

The modified-release formulations of the present invention can also beprovided as membrane modified formulations. Membrane-modifiedformulations of the present invention can be made by preparing a rapidrelease core, which can be a monolithic (e.g., tablet) or multi-unit(e.g., pellet) type, and coating the core with a membrane. Themembrane-modified core can then be further coated with a functionalcoating. In between the membrane-modified core and functional coating, abarrier or sealant can be applied. Details of membrane-modified dosageforms are provided below.

For example, the drug or pro-drug can be provided in a multiparticulatemembrane-modified formulation. The drug or pro-drug can be formed intoan active core by applying the compound to a nonpareil seed having anaverage diameter in the range of about 0.4 to about 1.1 mm, or about0.85 to about 1 mm. The drug or pro-drug can be applied with or withoutadditional excipients onto the inert cores, and can be sprayed fromsolution or suspension using a fluidized bed coater (e.g., Wurstercoating) or pan coating system. Alternatively, the drug or pro-drug canbe applied as a powder onto the inert cores using a binder to bind thedrug or pro-drug onto the cores. Active cores can also be formed byextrusion of the core with suitable plasticizers (described below) andany other processing aids as necessary.

The modified-release formulations of the present invention comprise atleast one polymeric material, which can be applied as a membrane coatingto the drug-containing cores. Suitable water-soluble polymers include,but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone,methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose,or polyethylene glycol, and/or mixtures thereof.

Suitable water-insoluble polymers include, but are not limited to,ethylcellulose, cellulose acetate, cellulose propionate, celluloseacetate propionate, cellulose acetate butyrate, cellulose acetatephthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethylmethacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate),and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly(lauryl methacrylate), poly (phenyl methacrylate), poly (methylacrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly(octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly(ethylene) high density, poly (ethylene oxide), poly (ethyleneterephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly(vinyl chloride), or polyurethane, and/or mixtures thereof.

EUDRAGIT™ polymers (available from Rohm Pharma) are polymeric lacquersubstances based on acrylates and/or methacrylates. A suitable polymerthat is freely permeable to the active ingredient and water is EUDRAGIT™RL. A suitable polymer that is slightly permeable to the activeingredient and water is EUDRAGIT™ RS. Other suitable polymers which areslightly permeable to the active ingredient and water, and exhibit apH-dependent permeability include, but are not limited to, EUDRAGIT™ L,EUDRAGIT™ S, and EUDRAGIT™ E.

EUDRAGIT™ RL and RS are acrylic resins comprising copolymers of acrylicand methacrylic acid esters with a low content of quaternary ammoniumgroups. The ammonium groups are present as salts and give rise to thepermeability of the lacquer films. EUDRAGIT™ RL and RS are freelypermeable (RL) and slightly permeable (RS), respectively, independent ofpH. The polymers swell in water and digestive juices, in apH-independent manner. In the swollen state, they are permeable to waterand to dissolved active compounds.

EUDRAGIT™ L is an anionic polymer synthesized from methacrylic acid andmethacrylic acid methyl ester. It is insoluble in acids and pure water.It becomes soluble in neutral to weakly alkaline conditions. Thepermeability of EUDRAGIT™ L is pH dependent. Above pH 5.0, the polymerbecomes increasingly permeable.

In one embodiment comprising a membrane-modified dosage form, thepolymeric material comprises methacrylic acid co-polymers, ammoniomethacrylate co-polymers, or a mixture thereof. Methacrylic acidco-polymers such as EUDRAGIT™ S and EUDRAGIT™ L (Rohm Pharma) areparticularly suitable for use in the modified-release formulations ofthe present invention. These polymers are gastroresistant andenterosoluble polymers. Their polymer films are insoluble in pure waterand diluted acids. They dissolve at higher pHs, depending on theircontent of carboxylic acid. EUDRAGIT™ S and EUDRAGIT™ L can be used assingle components in the polymer coating or in combination in any ratio.By using a combination of the polymers, the polymeric material canexhibit a solubility at a pH between the pHs at which EUDRAGIT™ L andEUDRAGIT™ S are separately soluble.

The membrane coating can comprise a polymeric material comprising amajor proportion (i.e., greater than 50% of the total polymeric content)of one or more pharmaceutically acceptable water-soluble polymers, andoptionally a minor proportion (i.e., less than 50% of the totalpolymeric content) of one or more pharmaceutically acceptablewater-insoluble polymers. Alternatively, the membrane coating cancomprise a polymeric material comprising a major proportion (i.e.,greater than 50% of the total polymeric content) of one or morepharmaceutically acceptable water-insoluble polymers, and optionally aminor proportion (i.e., less than 50% of the total polymeric content) ofone or more pharmaceutically acceptable water-soluble polymers.

Ammonio methacrylate co-polymers such as Eudragit RS and Eudragit RL(Rohm Pharma) are suitable for use in the modified-release formulationsof the present invention. These polymers are insoluble in pure water,dilute acids, buffer solutions, or digestive fluids over the entirephysiological pH range. The polymers swell in water and digestive fluidsindependently of pH. In the swollen state they are then permeable towater and dissolved actives. The permeability of the polymers depends onthe ratio of ethylacrylate (EA), methyl methacrylate (MMA), andtrimethylammonioethyl methacrylate chloride (TAMCl) groups in thepolymer. Those polymers having EA:MMA:TAMCl ratios of 1:2:0.2 (EudragitRL) are more permeable than those with ratios of 1:2:0.1 (Eudragit RS).Polymers of Eudragit RL are insoluble polymers of high permeability.Polymers of Eudragit RS are insoluble films of low permeability.

The ammonio methacrylate co-polymers can be combined in any desiredratio. For example, a ratio of Eudragit RS:Eudragit RL (90:10) can beused. The ratios can furthermore be adjusted to provide a delay inrelease of the drug or pro-drug. For example, the ratio of EudragitRS:Eudragit RL can be about 100:0 to about 80:20, about 100:0 to about90:10, or any ratio in between. In such formulations, the less permeablepolymer Eudragit RS would generally comprise the majority of thepolymeric material.

The ammonio methacrylate co-polymers can be combined with themethacrylic acid co-polymers within the polymeric material in order toachieve the desired delay in release of the drug or pro-drug. Ratios ofammonio methacrylate co-polymer (e.g., Eudragit RS) to methacrylic acidco-polymer in the range of about 99:1 to about 20:80 can be used. Thetwo types of polymers can also be combined into the same polymericmaterial, or provided as separate coats that are applied to the core.

In addition to the Eudragit polymers described above, a number of othersuch copolymers can be used to control drug release. These includemethacrylate ester co-polymers (e.g., Eudragit NE 30D). Furtherinformation on the Eudragit polymers can be found in “Chemistry andApplication Properties of Polymethacrylate Coating Systems,” in AqueousPolymeric Coatings for Pharmaceutical Dosage Forms (ed. James McGinity,Marcel Dekker Inc., New York, pg 109-114).

The coating membrane can further comprise one or more soluble excipientsso as to increase the permeability of the polymeric material. Suitably,the soluble excipient is selected from among a soluble polymer, asurfactant, an alkali metal salt, an organic acid, a sugar, and a sugaralcohol. Such soluble excipients include, but are not limited to,polyvinyl pyrrolidone, polyethylene glycol, sodium chloride, surfactantssuch as sodium lauryl sulfate and polysorbates, organic acids such asacetic acid, adipic acid, citric acid, fumaric acid, glutaric acid,malic acid, succinic acid, and tartaric acid, sugars such as dextrose,fructose, glucose, lactose and sucrose, sugar alcohols such as lactitol,maltitol, mannitol, sorbitol and xylitol, xanthan gum, dextrins, andmaltodextrins. In some embodiments, polyvinyl pyrrolidone, mannitol,and/or polyethylene glycol can be used as soluble excipients. Thesoluble excipient(s) can be used in an amount of from about 0.5% toabout 80% by weight, based on the total dry weight of the polymer.

In another embodiment, the polymeric material comprises one or morewater-insoluble polymers, which are also insoluble in gastrointestinalfluids, and one or more water-soluble pore-forming compounds. Forexample, the water-insoluble polymer can comprise a terpolymer ofpolyvinylchloride, polyvinylacetate, and/or polyvinylalcohol. Suitablewater-soluble pore-forming compounds include, but are not limited to,saccharose, sodium chloride, potassium chloride, polyvinylpyrrolidone,and/or polyethyleneglycol. The pore-forming compounds can be uniformlyor randomly distributed throughout the water-insoluble polymer.Typically, the pore-forming compounds comprise about 1 part to about 35parts for each about 1 to about 10 parts of the water-insolublepolymers.

When such dosage forms come in to contact with the dissolution media(e.g., intestinal fluids), the pore-forming compounds within thepolymeric material dissolve to produce a porous structure through whichthe drug diffuses. Such formulations are described in more detail inU.S. Pat. No. 4,557,925, which relevant part is incorporated herein byreference for this purpose. The porous membrane can also be coated withan enteric coating, as described herein, to inhibit release in thestomach.

For example, a pore forming modified release dosage form can comprisedrug or pro-drug; a filler, such as starch, lactose, or microcrystallinecellulose (AVICEL™); a binder/modified release polymer, such ashydroxypropyl methylcellulose or polyvinyl pyrrolidone; a disintegrant,such as, EXPLOTAB™, crospovidone, or starch; a lubricant, such asmagnesium stearate or stearic acid; a surfactant, such as sodium laurylsulfate or polysorbates; and a glidant, such as colloidal silicondioxide (AEROSIL™) or talc.

The polymeric material can also include one or more auxiliary agentssuch as fillers, plasticizers, and/or anti-foaming agents.Representative fillers include talc, fumed silica, glycerylmonostearate, magnesium stearate, calcium stearate, kaolin, colloidalsilica, gypsum, micronized silica, and magnesium trisilicate. Thequantity of filler used typically ranges from about 0.5% to about 300%by weight, and can range from about 0.5% to about 100%, based on thetotal dry weight of the polymer. In one embodiment, talc is the filler.

The coating membranes, and functional coatings as well, can also includea material that improves the processing of the polymers. Such materialsare generally referred to as plasticizers and include, for example,adipates, azelates, benzoates, citrates, isoebucates, phthalates,sebacates, stearates and glycols. Representative plasticizers includeacetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyltartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethylglycolate, glycerin, ethylene glycol, propylene glycol, triacetincitrate, triacetin, tripropinoin, diacetin, dibutyl phthalate, acetylmonoglyceride, polyethylene glycols, castor oil, triethyl citrate,polyhydric alcohols, acetate esters, gylcerol triacetate, acetyltriethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octylphthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate,epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate,di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate,di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyltrimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate,di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate, andglyceryl monocaprate. In one embodiment, the plasticizer is dibutylsebacate. The amount of plasticizer used in the polymeric materialtypically ranges from about 0.5% to about 50%, for example, about 0.5,1, 2, 5, 10, 20, 30, 40, or 50%, based on the weight of the dry polymer.

Anti-foaming agents can also be included. In one embodiment, theanti-foaming agent is simethicone. The amount of anti-foaming agent usedtypically comprises from about 0% to about 0.5% of the finalformulation.

The amount of polymer to be used in the membrane modified formulationsis typically adjusted to achieve the desired drug delivery properties,including the amount of drug to be delivered, the rate and location ofdrug delivery, the time delay of drug release, and the size of themultiparticulates in the formulation. The amount of polymer appliedtypically provides an about 0.5% to about 100% weight gain to the cores.In one embodiment, the weight gain from the polymeric material rangesfrom about 2% to about 70%.

The combination of all solid components of the polymeric material,including co-polymers, fillers, plasticizers, and optional excipientsand processing aids, typically provides an about 0.5% to about 450%weight gain on the cores. In one embodiment, the weight gain is about 2%to about 160%.

The polymeric material can be applied by any known method, for example,by spraying using a fluidized bed coater (e.g., Wurster coating) or pancoating system. Coated cores are typically dried or cured afterapplication of the polymeric material. Curing means that themultiparticulates are held at a controlled temperature for a timesufficient to provide stable release rates. Curing can be performed, forexample, in an oven or in a fluid bed drier. Curing can be carried outat any temperature above room temperature.

A sealant or barrier can also be applied to the polymeric coating. Asealant or barrier layer can also be applied to the core prior toapplying the polymeric material. A sealant or barrier layer is notintended to modify the release of drug or pro-drug. Suitable sealants orbarriers are permeable or soluble agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose,and xanthan gum.

Other agents can be added to improve the processability of the sealantor barrier layer. Such agents include talc, colloidal silica, polyvinylalcohol, titanium dioxide, micronized silica, fumed silica, glycerolmonostearate, magnesium trisilicate and magnesium stearate, or a mixturethereof. The sealant or barrier layer can be applied from solution(e.g., aqueous) or suspension using any known means, such as a fluidizedbed coater (e.g., Wurster coating) or pan coating system. Suitablesealants or barriers include, for example, OPADRY WHITE Y-1-7000 andOPADRY OY/B/28920 WHITE, each of which is available from ColorconLimited, England.

The invention also provides an oral dosage form containing amultiparticulate drug or pro-drug formulation as hereinabove defined, inthe form of caplets, capsules, particles for suspension prior to dosing,sachets, or tablets. When the dosage form is in the form of tablets, thetablets can be disintegrating tablets, fast dissolving tablets,effervescent tablets, fast melt tablets, and/or mini-tablets. The dosageform can be of any shape suitable for oral administration of a drug,such as spheroidal, cube-shaped, oval, or ellipsoidal. The dosage formscan be prepared from the multiparticulates in any known manner and caninclude additional pharmaceutically acceptable excipients.

All of the particular embodiments described above, including but notlimited to, matrix-based, osmotic pump-based, soft gelatin capsules,and/or membrane-modified forms, which can further take the form ofmonolithic and/or multi-unit dosage forms, can have a functionalcoating. Such coatings generally serve the purpose of delaying therelease of the drug for a predetermined period. For example, suchcoatings can allow the dosage form to pass through the stomach withoutbeing subjected to stomach acid or digestive juices. Thus, such coatingscan dissolve or erode upon reaching a desired point in thegastrointestinal tract, such as the upper intestine.

Such functional coatings can exhibit pH-dependent or pH-independentsolubility profiles. Those with pH-independent profiles generally erodeor dissolve away after a predetermined period, and the period isgenerally directly proportional to the thickness of the coating. Thosewith pH-dependent profiles, on the other hand, can maintain theirintegrity while in the acid pH of the stomach, but quickly erode ordissolve upon entering the more basic upper intestine.

Thus, a matrix-based, osmotic pump-based, or membrane-modifiedformulation can be further coated with a functional coating that delaysthe release of the drug. For example, a membrane-modified formulationcan be coated with an enteric coating that delays the exposure of themembrane-modified formulation until the upper intestine is reached. Uponleaving the acidic stomach and entering the more basic intestine, theenteric coating dissolves. The membrane-modified formulation then isexposed to gastrointestinal fluid, and releases drug or pro-drug over anextended period, in accordance with the invention. Examples offunctional coatings such as these are known in the art.

The thickness of the polymer in the formulations, the amounts and typesof polymers, and the ratio of water-soluble polymers to water-insolublepolymers in the modified-release formulations are generally selected toachieve a desired release profile of drug or pro-drug. For example, byincreasing the amount of water-insoluble-polymer relative to thewater-soluble polymer, the release of the drug can be delayed or slowed.

Immediate-release formulations according to the present invention, whenmeasured by a U.S. Pharmacopoeia (USP) Type 1 Apparatus (baskets) orU.S. Pharmacopeia (USP) Type 2 Apparatus (paddles) at 37° C. and 50 rpmor higher in phosphate buffer at pH 6.8 or higher for the measuringperiod, can exhibit the following dissolution profile: about 45% or moreis released in about 1 hour or less, about 80% or more is released inabout 2 hours or less, and about 100% or more is released in about 3hours or less.

The present inventive methods and formulations also providepH-independent modified-release formulations comprising drug orpro-drug, or a pharmaceutically acceptable salt thereof, that whenmeasured by a U.S. Pharmacopoeia (USP) Type 1 Apparatus (baskets) orU.S. Pharmacopoeia (USP) Type 2 Apparatus (paddles) at 37° C. and 50 rpmor higher in phosphate buffer at pH 6.8 or higher for the measuringperiod, release less than or equal to about 30%, less than about 20%, orless than about 10% of the drug or pro-drug, in vitro in less than about1 hours; release less than or equal to about 60%, less than about 50%,or less than about 40%, in about 4 or more hours; and release greaterthan or equal to about 70%, greater than about 80%, or greater thanabout 90% in about 12 or more hours.

More particularly, pH-independent modified-release formulationsaccording to the present invention can exhibit dissolution profiles,when measured by a U.S. Pharmacopoeia (USP) Type 1 Apparatus (baskets)or U.S. Pharmacopoeia (USP) Type 2 Apparatus (paddles) at 37° C. and 50rpm or higher in phosphate buffer at pH 6.8 or higher for the measuringperiod, falling within the following windows: 1 hour: less than or equalto about 20%; 2 hours: from about 0 to about 35%; 3 hours: from about 10to about 60%; 4 hours: from about 20 to about 60%; 6 hours: from about40 to about 80%; and 12 hours: greater than or equal to about 75%. Inother embodiments, the dissolution profiles can fall within thefollowing windows: 1 hour: less than or equal to about 5%; 2 hours: fromabout 0 to about 25%; 3 hours: from about 15 to about 30%; 4 hours: fromabout 40 to about 50%; 6 hours: from about 60 to about 75%; and 12hours: greater than or equal to about 90%. Note that formulations ofthis invention may fall within one or more of these dissolution windows.

Formulations, which can be pH-dependent modified-release formulations,according to the present invention, when measured by a U.S.Pharmacopoeia (USP) Type 1 Apparatus (baskets) or U.S. Pharmacopoeia(USP) Type 2 Apparatus (paddles) at 37° C. and 50 rpm or higher in 0.01to 0.1 N HCl for two hours, followed by phosphate buffer at pH 6.8 orhigher for the remaining measuring period, can exhibit dissolutionprofiles falling within one or more of these dissolution windows: 1 hour(in acid), about 0 to about 10% released; 2 hours (in acid), about 0 toabout 10% released; 1 hour (in buffer), about 10 to about 35% released;2 hours (in buffer), about 20 to about 65% released; 4 hours (inbuffer), about 55 to about 95% released; 6 hours (in buffer), greaterthan or equal to about 90% released; and 12 hours (in buffer), about 90%or greater released. In other embodiments, the inventive formulationscan exhibit dissolution profiles falling within one or more of thesedissolution windows: 1 hour (in acid), about 0 to about 5% released; 2hours (in acid), about 0 to about 5% released; 1 hour (in buffer), about15 to about 30% released; 2 hours (in buffer), about 25 to about 60%released; 4 hours (in buffer), about 60 to about 90% released; 6 hours(in buffer), greater than or equal to about 90% released; and 12 hours(in buffer), about 95% or greater released. Again, it should be notedthat formulations of this invention may fall within one or more of thesedissolution windows.

The present invention overcomes the deficiencies and problems in theprior art by providing new and effective formulations and methods forreducing, preventing, and/or managing inflammatory bowel disease, andsymptoms thereof. The methods for reducing, preventing, and/or managinginflammatory bowel disease involve administering an effective amount ofa drug or pro-drug, or a pharmaceutically acceptable salt thereof, to asubject in need of such reduction, prevention, and/or management. Theinflammatory bowel disease can be associated with one or more intestinalconditions. Thus, the present invention can also be used to directly orindirectly reduce, prevent, and/or manage such intestinal conditions bythe use of these drugs or pro-drugs. Examples of intestinal conditionsthat can be treated, prevented, and/or managed according to the presentinvention include, but are not limited to, inflammatory bowel disease(IBD), ulcerative colitis, granulomatous enteritis, Crohn's disease,infectious diseases of the small and large intestine, pyloric spasm,abdominal cramps, functional gastrointestinal disorders, milddysenteries, diverticulitis, acute enterocolitis, neurogenic boweldisorders, including the splenic flexure syndrome and neurogenic colon,spastic colitis, cysts, polyps, and carcinoma, and/or symptoms of any ofthe foregoing. Those of ordinary skill in the art will be familiar withother types of intestinal conditions that produce inflammatory boweldisease, which can benefit from the present invention.

As used herein, the term “pharmaceutically acceptable salt” includessalts that are physiologically tolerated by a subject. Such salts can beprepared from an inorganic and/or organic acid. Examples of suitableinorganic acids include, but are not limited to, hydrochloric,hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric acid. Organicacids can be aliphatic, aromatic, carboxylic, and/or sulfonic acids.Suitable organic acids include, but are not limited to, formic, acetic,propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, lactic,malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic,maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic,mandelic, pamoic, methanesulfonic, ethanesulfonic, pantothenic,benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic,and the like.

In accordance with the invention, the drug or pro-drug, or apharmaceutically acceptable salt thereof, is formulated and/or dosed ina manner that maximizes its therapeutic effects, while minimizing atleast one systemic side effect.

The present invention also provides methods and formulations fortreating inflammatory bowel disease, comprising administering to saidsubject an effective amount of the drug or pro-drug, or apharmaceutically acceptable salt thereof, in combination with at leastone additional pharmaceutically active compound. Examples of otherpharmaceutically active compounds that can be used in combination withthe drug or pro-drug include, but are not limited to, steroids (forexample, budesonide and other corticosteroids, and adrenal steroids suchas prednisone and hydrocortisone), cytokines such as interleukin-10,antibiotics, immunomodulating agents such as azathioprine,6-mercaptopurine, methotrexate, cyclosporine, and anti-tumor necrosisfactor (TNF) agents such as soluble TNF receptor and antibodies raisedto TNF, and also antinflammatory agents such as zinc.

The drug or pro-drug, or a pharmaceutically acceptable salt thereof, canbe administered with one or more of such pharmaceutically activecompounds. Combinations can be administered such that drug or pro-drug,or a pharmaceutically acceptable salt thereof, and the at least oneother pharmaceutically active compound are contained in the same dosageform. Alternatively, the combinations can be administered such that drugor pro-drug and the at least one additional pharmaceutically activecompound are contained in separate dosage forms and are administeredconcomitantly or sequentially.

The drug or pro-drug used in accordance with the present invention canbe obtained by any method. Examples of such methods are described in,for example, U.S. Pat. Nos. 4,591,584, 4,559,330, and 6,602,915, each ofwhich is incorporated herein by reference for this purpose.Modifications of the protocols described in these patents, as well asother routes of synthesis, are well known to those of ordinary skill inthe art and can be employed in accordance with the present invention.

The pharmaceutically acceptable formulations described herein can beprovided in the form of a pharmaceutical formulation for use accordingto the present invention. Such formulations optionally include one ormore pharmaceutically acceptable excipients. Examples of suitableexcipients are known to those of skill in the art and are described, forexample, in the Handbook of Pharmaceutical Excipients (Kibbe (ed.),3^(rd) Edition (2000), American Pharmaceutical Association, Washington,D.C.), and Remington: The Science and Practice of Pharmacy (Gennaro(ed.), 20^(th) edition (2000), Mack Publishing, Inc., Easton, Pa.)(hereinafter referred to as “Remington”), both of which, for theirdisclosures relating to excipients and dosage forms, are incorporatedherein by reference. Suitable excipients include, but are not limitedto, starches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, wetting agents,emulsifiers, coloring agents, release agents, coating agents, sweeteningagents, flavoring agents, perfuming agents, preservatives, plasticizers,gelling agents, thickeners, hardeners, setting agents, suspendingagents, surfactants, humectants, carriers, stabilizers, antioxidants,and combinations thereof.

Formulations suitable for oral administration include, but are notlimited to, capsules, cachets, pills, tablets, lozenges (using aflavored base, usually sucrose and acacia or tragacanth), powders,granules, solutions, suspensions in an aqueous or non-aqueous liquid,oil-in-water or water-in-oil liquid emulsions, elixirs, syrups,pastilles (using an inert base, such as gelatin and glycerin, or sucroseand acacia), mouth washes, pastes, and the like, each containing apredetermined amount of drug or pro-drug, or a pharmaceuticallyacceptable salt thereof, to provide a therapeutic amount of the drug inone or more doses.

The drug or pro-dug, or a pharmaceutically acceptable salt thereof, canbe mixed with pharmaceutically acceptable excipients in the preparationof dosage forms for oral administration (capsules, tablets, pills,powders, granules and the like). Suitable excipients include, but arenot limited to, carriers, such as sodium citrate or dicalcium phosphate;fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, or silicic acid; binders, such as hydroxymethyl-cellulose,alginates, gelatin, polyvinylpyrrolidone, sucrose or acacia; humectants,such as glycerol; disintegrating agents, such as agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates, orsodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol or glycerol monostearate; absorbents, suchas kaolin and bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, and sodiumlauryl sulfate; coloring agents; buffering agents; dispersing agents;preservatives; and diluents.

The aforementioned excipients are given as examples only and are notmeant to include all possible choices. Solid formulations can also beemployed as fillers in soft and hard-filled gelatin capsules usingexcipients such as lactose or milk sugars, high molecular weightpolyethylene glycols, and the like. Any of these dosage forms canoptionally be scored or prepared with coatings and shells, such asenteric coatings and coatings for modifying the rate of release,examples of which are well known in the pharmaceutical-formulating art.

Such coatings can comprise sodium carboxymethylcellulose, celluloseacetate, cellulose acetate phthalate, ethylcellulose, gelatin,pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose phthalate, methacrylicacid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetatephthalate, shellac, sucrose, titanium dioxide, wax, or zein. In oneembodiment, the coating material comprises hydroxypropylmethylcellulose. The coating material can further compriseanti-adhesives, such as talc; plasticizers (depending on the type ofcoating material selected), such as castor oil, diacetylatedmonoglycerides, dibutyl sebacate, diethyl phthalate, glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate;opacifiers, such as titanium dioxide; and/or coloring agents and/orpigments. The coating process can be carried out by any suitable means,for example, by using a perforated pan system such as the GLATTT™,ACCELACOTA™, and/or HICOATER™ apparatuses.

Tablets can be formed by any suitable process, examples of which areknown to those of ordinary skill in the art. For example, theingredients can be dry-granulated or wet-granulated by mixing in asuitable apparatus before tabletting. Granules of the ingredients to betabletted can also be prepared using suitable spray/fluidization orextrusion/spheronization techniques.

The tablets can be formulated with suitable excipients to act as a fastdissolving and/or fast melting tablet in the oral cavity. Also, thetablet can be in the form of a chewable or effervescent dosage form.With effervescent dosage forms, the tablet can be added to a suitableliquid that causes it to disintegrate, dissolve, and/or disperse.

Tablets can be designed to have an appropriate hardness and friabilityto facilitate manufacture on an industrial scale using equipment toproduce tablets at high speed. Also, the tablets can be packed or filledin any kind of container. It should be noted that the hardness oftablets, amongst other properties, can be influenced by the shape of thetablets. Different shapes of tablets can be used according to thepresent invention. Tablets can be circular, oblate, oblong, or any othershape. The shape of the tablets can also influence the disintegrationrate.

Any of the inventive formulations can be encapsulated in soft and hardgelatin capsules, which can also include any of the excipients describedabove. For example, the encapsulated dosage form can include fillers,such as lactose and microcrystalline; glidants, such as colloidalsilicon dioxide and talc; lubricants, such as magnesium stearate; anddisintegrating agents, such as starch (e.g., maize starch). Usingcapsule filling equipment, the ingredients to be encapsulated can bemilled together, sieved, mixed, packed together, and then delivered intoa capsule. Lubricants can be present in an amount of from about 0.5%(w/w) to about 2.0% (w/w).

The formulations of the invention, which comprise drug or pro-drug, or apharmaceutically acceptable salt thereof, can also be formulated into aliquid dosage form for oral administration. Suitable formulations caninclude emulsions, microemulsions, solutions, suspensions, syrups, andelixirs. The drug or pro-drug can be formulated as an ion-exchange resincomplex, a microencapsulated particle, a liposome particle, or a polymercoated particle or granule. These formulations optionally includediluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers. Emulsifiers include, butare not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils, glycerol, tetrahydrofurfuryl alcohol,polyethylene glycols, fatty acid esters of sorbitan, and mixturesthereof. In addition, the inventive formulations can include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming, and preservative agents. Suitablesuspension agents include, but are not limited to, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth, and mixtures thereof. The liquid formulations can bedelivered as-is, or can be provided in hard or soft capsules, forexample.

The amount of suspending agent present will vary according to theparticular suspending agent used, and the presence or absence of otheringredients that have an ability to act as a suspending agent orcontribute significantly to the viscosity of the formulation. Thesuspension can also contain ingredients that improve its taste, forexample sweeteners; bitter-taste maskers, such as sodium chloride;taste-masking flavors, such as contramarum; flavor enhancers, such asmonosodium glutamate; and flavoring agents. Examples of sweetenersinclude bulk sweeteners, such as sucrose, hydrogenated glucose syrup,the sugar alcohols sorbitol and xylitol; and sweetening agents such assodium cyclamate, sodium saccharin, aspartame, and ammoniumglycyrrhizinate. The liquid formulations can further comprise one ormore buffering agents, as needed, to maintain a desired pH.

The liquid formulations of the present invention can also be filled intosoft gelatin capsules. The liquid can include a solution, suspension,emulsion, microemulsion, precipitate, or any other desired liquid mediacarrying the pharmaceutically active compound. The liquid can bedesigned to improve the solubility of the pharmaceutically activecompound upon release, or can be designed to form a drug-containingemulsion or dispersed phase upon release. Examples of such techniquesare well known in the art. Soft gelatin capsules can be coated, asdesired, with a functional coating. Such functional coatings generallyserve the purpose of delaying the release of the drug for apredetermined period. For example, such coatings can allow the dosageform to pass through the stomach without being subjected to stomach acidor digestive juices. Thus, such coatings can dissolve or erode uponreaching a desired point in the gastrointestinal tract, such as theupper intestine.

For rectal administration, the inventive formulations can be provided asa suppository. Suppositories can comprise one or more non-irritatingexcipients such as, for example, polyethylene glycol, a suppository wax,or a salicylate. Such excipients can be selected on the basis ofdesirable physical properties. For example, a compound that is solid atroom temperature but liquid at body temperature will melt in the rectumand release the active compound. The formulation can alternatively beprovided as an enema for rectal delivery.

The amount of the dose administered, as well as the dose frequency, willvary depending on the particular dosage form used and the route ofadministration. The amount and frequency of administration will alsovary according to the age, body weight, and response of the individualsubject. Typical dosing regimens can readily be determined by acompetent physician without undue experimentation. It is also noted thatthe clinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual subjectresponse.

In general, the total daily dosage for reducing, preventing, and/ormanaging the inflammatory bowel disease and/or the intestinal conditionsthat cause the same, with any of the formulations according to thepresent invention, is from about 250 mg to about 8000 mg, or from about500 mg to about 8000 mg, or from about 1000 mg to about 6000 mg, or fromabout 2000 mg to about 4000 mg. Pro-drugs should be formulated todeliver an equivalent dose. A single oral dose can be formulated tocontain about 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg,or 3000 mg, or any amount in between.

The pharmaceutical formulations containing drug and/or pro-drug, or apharmaceutically acceptable salt thereof, can be administered in singleor divided doses, 1, 2, 3, 4, 5, or more times each day. Alternatively,the dose can be delivered one or more times every 2, 3, 4, 5, 6, 7, ormore days. In one embodiment, the pharmaceutical formulations areadministered once per day.

The invention is further illustrated by reference to the followingexamples. It will be apparent to those skilled in the art that manymodifications, both to the materials and methods, can be practicedwithout departing from the purpose and scope of the invention.

EXAMPLES Example 1 Effect of Disodium 4,4′-Azo-Bis Salicylate onInflammatory Bowel Disease

A subject is diagnosed with mild to moderate ulcerative colitis orCrohn's Disease. The subject receives a daily administration of 2 gramsper day of disodium 4,4′-azo-bis salicylate. The subject is treated for12 weeks. The subject keeps daily diaries and records the number andnature of bowel movements. The effect of the treatments is assessed bygrading clinical symptoms of fecal blood, mucus, and urgency. Inaddition, sigmoidoscopic assessment and biopsies are performed, andefficacy of treatment assessed, based on grading of sigmoidoscopic anddegree of histological inflammation in rectal biopsy specimens. Safetyis assessed based on spontaneous side effect reporting.

Example 2 Modified Release Matrix Tablet Formulations of4-Aminosalicylate Sodium Using Methocel Premium Wet Granulation Method

The 4-aminosalicylate sodium is formulated in a matrix tablet thatachieves the following target dissolution profiles.

Target Dissolution Profiles

Matrix Tablet without functional coating.

Time (Hours) pH 6.8 Buffer % Released 1 20 2 35 3 55 4 60 6 72 12 100

Matrix Tablet with functional coating (pH-independent Type A).

Time (Hours) pH 6.8 Buffer % Released 1 0 2 22 3 30 4 55 6 68 12 95

Matrix Tablet with functional coating (pH-independent Type B).

Time (Hours) pH 6.8 Buffer % Released 1 0 2 0 3 14 4 22 6 41 12 76

Matrix Tablet with functional coating (pH-dependent).

Time (Hours) % Released Acid 1 0 2 0 pH 6.8 Buffer 1 12 2 27 4 63 6 91

Matrix Tablet Formulation

The uncoated Matrix Tablet Formulation and processing details are givenbelow.

Composition

Ingredient FUNCTION Mg/tab Mg/tab Mg/tab 4 Aminosalicylate Sodium Active571.76 571.76 571.76 LACTOSE Diluent 78.12 28.12 12.12 AVICEL PH 101Binder diluent 78.12 28.12 12.12 METHOCEL Controlled 200.00 300.00400.00 *PREMIUM CR Release Polymer COLLOIDAL Glidant 2.00 2.00 2.00SILICON DIOXIDE STEARIC ACID Lubricant 20.0 20.00 20.0 PVP Binder 50.050.0 50.0 *ISOPROPYL ALCOHOL Solvent N/A N/A N/A TOTAL (mg) N/A 10001000 1068 *Methocel grade can be changed or alternatively can be asuitable controlled-release polymer from the example list.

Process—Wet Granulation Process (Using Composition above)

1. The ingredients are weighed.

2. The Active, 50% of the Avicel, and 50% of the Lactose are placed in asuitable mixer. (For example, Planetary (Hobart), High Shear(Diosna/Fielder)).

3. The ingredients are mixed for 15 minutes to produce a homogeneousmixture.

4. Mixing is continued, while adding to the mixture the granulatingfluid (Sodium/PVP Solution).

5. The ingredients are mixed until a suitable granulation end-point isachieved (add more IPA if needed to produce a suitable granule).

6. The granules are dried (using an oven or fluidization equipment)until an acceptable level of moisture (<about 1%) and IPA (<about 0.5%)is achieved. An infrared moisture balance can be used to ascertain watercontent, and a gas chromatograph can be used for organic solvents.

7. The dry granulate is passed through suitable comminution equipment(for example, Co-Mill or Fitzpatrick mill) fitted with a suitable sizedscreen (100-500 micron).

8. The granulate is placed in a blender, and the colloidal SiliconDioxide and the remainder of the Lactose and Avicel are added.

9. The mixture is blended for 15 minutes.

10. The Stearic Acid is added and mixed for 5 more minutes.

11. The mixture is compressed into oval shaped tablets (target weight1000 mg) on a suitable tablet machine.

Alternatively, the 4-aminosalicylate sodium can be dissolved in the IPA(or alternative solvent), and the PVP can be mixed in the dry blend(prior to granulation).

Functional Coating of the Matrix Tablet

The above-described matrix tablet formulation can be coated with afunctional coat. This may be pH-dependent or pH-independent. Examples ofboth types of coating are given below.

pH-Independent Coating

Two types of pH-independent polymer systems are described, that can beused for coating the matrix tablets described above. (Note that althoughthey are described as being used in a matrix system, these coatings canbe used in non-matrix systems, including the coating ofimmediate-release systems.)

Composition—Polymer System A

Ingredient FUNCTION (Batch g) METHOCEL Controlled 750.00 Release PolymerETHOCEL Controlled 250.0 Release Polymer TRIETHYL CITRATE Plasticizer12.00 IPA Solvent 2000 TOTAL 3012

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. When the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

Composition—Polymer System B

Ingredient FUNCTION (Batch g) EUDRAGIT RS 12.5 Controlled 900.00 ReleasePolymer EUDRAGIT RL 12.5 Controlled 300.00 Release Polymer TALCAntiadherent 105.00 DIBUTYL SEBECATE Plasticizer 15.00 MAGNESIUMSTEARATE Antiadherant 30.00 ACETONE Solvent 825.00 ISOPROPYL ALCOHOLSolvent 825 TOTAL 3000.00

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried in the coating machine.

pH-Dependent Coating

Qty % Batch 1 Ingredient FUNCTION (w/w) mg/tab EUDRAGIT L 100 Polymer6.39 6.00 ACETYL TRIBUTYL CITRATE Plasticizer 1.60 1.50 WATER* Solvent3.26 N/A ETHANOL* Solvent 88.75 N/A TOTAL 100.00

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried in a coating machine.

Example 3 Modified Release Formulations of 4-Aminosalicylate SodiumUsing a Membrane-Modified Tablet

The 4-aminosalicylate sodium is formulated in a Membrane-Modified Tabletto achieve the following dissolution profiles.

Target Dissolution Profiles

Membrane-Modified Tablet without functional coating.

Time (Hours) pH 6.8 Buffer % Released 1 45 2 80 3 100

Membrane-Modified Tablet with functional coating (pH independent TypeA).

Time (Hours) pH 6.8 Buffer % Released 1 0 2 13 3 24 4 37 6 61 12 90

Membrane-Modified Tablet with functional coating (pH-independent TypeB).

Time (Hours) pH 6.8 Buffer % Released 1 0 2 0 3 21 4 44 6 80 12 100

Membrane-Modified Tablet with functional coating (pH-dependent).

Time (Hours) % Released Acid 1 0 2 0 pH 6.8 Buffer 1 30 2 58 4 91 6 100

In each of these examples, the product comprises an instant-releasetablet core coated with the diffusion-controlled Membrane. Theformulations and manufacturing process for these are given below.

Instant-Release Core Formulation

Composition

Qty Qty Ingredient FUNCTION mg/tab Batch g 4AMINOSALICYLATE SODIUMActive 571.76 571.76 LACTOSE ANHYDROUS Diluent 86.12 86.12MICROCRYSTALLINE CELLULOSE Diluent 86.12 86.12 PVP K30 Binder 40.0 40.0STEARIC ACID Lubricant 16.0 16.0 TOTAL 800.00 800.00

Process

Option 1:

1. The ingredients are weighed using a suitable balance.

2. The 4-aminosalicylate Sodium, Avicel, and Lactose are placed into asuitable granulator (e.g., high shear mixer-Diosna/Fielder).

3. Mix until a homogeneous blend is produced.

4. The PVP is dissolved in water and slowly add to the powder blend.

5. Once all the binder solution has been added to the powder blend,mixing is continued until a suitable granulation as been achieved.

6. The granules are dried in a fluidized drying machine or tray drieruntil a suitable dryness is achieved. An infrared moisture balance canbe used to ascertain water content, and a gas chromatograph can be usedfor organic solvents.

7. The dry granulate is then milled.

8. The dry granulate is placed in a suitable blender (V or Y typeblender), and the lubricant is added and mixed for 5 minutes.

9. The mixture is compressed into tablets (800 mg weight) on a suitabletablet machine.

Option 2:

Alternatively, 50% of the Lactose and Avicel can be used in Step 2 ofthe process. Once the dry granulate is produced, the remaining 50% ofthe Lactose and Avicel can be added to the mixer, mixed for 10 minutes.Then proceed to step 9 of the process described for Option 1.

Option 3:

In another alternative, the Active, Lactose, Avicel, and the PVP can bedry granulated, i.e., compressed into a dry granulator using a rollercompactor. The roller compacted material can then be passed through asuitable screen to produce granules. These granules can then be mixedwith the lubricant (i.e., Stearic acid) as in step 9 of the process.

Diffusion-Controlled Membrane Coating Formulation

Composition

Option Option Option A B C Ingredient mg/tab) mg/tab mg/tab POLYMER11.00 9.20 11.00 SUCROSE 29.00 17.00 21.00 ACETYL TRIBUTYL CITRATE 2.001.60 1.90 CASTOR OIL POLYMERISED 1.00 1.2 1.4 SODIUM HYDROGEN CARBONATE1.00 1.00 1.00 ACETONE* N/A N/A N/A TOTAL Polymer = terpolymer ofpolyvinyl chloride, polyvinyl acetate and polyvinyl alcohol (terpolymerPVC/PVAc/PVOH) *Solvent is removed during processing.

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

Functional Coating of the Membrane-Modified Tablet

The above selectively permeable membrane tablet formulation (i.e., thediffusion-controlled membrane-coated tablet) can be additionally coatedwith a functional coat. This may be pH-dependent or pH-independent.Examples of both types of coating are given below.

pH-Dependant Coating

Composition

Qty % Ingredient FUNCTION (w/w) EUDRAGIT L 100 Polymer 6.39 ACETYLTRIBUTYL CITRATE Plasticizer 1.60 WATER* Solvent 3.26 ETHANOL* Solvent88.75 TOTAL 100.00

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

pH-Independent Coating System

Two types of pH-independent polymer systems are described for use incoating the tablets described above.

Composition—Polymer System A

Ingredient FUNCTION (Batch g) ETHOCEL Controlled 760.00 Release PolymerMETHOCEL Controlled 330.0 Release Polymer ACETYL TRIBUTYL Plasticizer220.00 CITRATE ETHANOL Solvent 2680 WATER Solvent 451 TOTAL 4441

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

Composition—Polymer System B

Ingredient FUNCTION (Batch g) EUDRAGIT RS 12.5 Controlled 900.00 ReleasePolymer EUDRAGIT RL 12.5 Controlled 300.00 Release Polymer TALC Antadherent 105.00 DIBUTYL SEBECATE Plasticizer 15.00 MAGNESIUM STEARATEAntiadherant 30.00 ACETONE Solvent 825.00 ISOPROPYL ALCOHOL Solvent 825TOTAL 3000.0

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

Example 4 Modified Release Disodium 4,4′-Azo-Bis-SalicylateMembrane-Modified Tablet Formulations

The disodium 4,4′-azo-bis-4-aminosalicylate sodium is formulated as aModified-Release tablet using a diffusion-controlled membrane, with thefollowing target dissolution profiles.

Target Dissolution Profiles

Membrane-Modified Tablet without functional coating.

Time (Hours) pH 6.8 Buffer % Released 1 45 2 80 3 100

Membrane-Modified Tablet with functional coating (pH independent TypeA).

Time (Hours) pH 6.8 Buffer % Released 1 0 2 13 3 24 4 37 6 61 12 90

Membrane-Modified Tablet with functional coating (pH-independent TypeB).

Time (Hours) pH 6.8 Buffer % Released 1 0 2 0 3 21 4 44 6 80 12 100

Membrane-Modified Tablet with functional coating (pH-dependent).

Time (Hours) % Released Acid 1 0 2 0 pH 6.8 Buffer 1 30 2 58 4 91 6 100

Instant Release Core Formulation

Composition

Qty Qty Ingredient FUNCTION mg/tab Batch g Azo-bis-4 AminoSalicylateSodium Active 571.76 571.76 LACTOSE ANHYDROUS Diluent 86.12 86.12MICROCRYSTALLINE CELLULOSE Diluent 86.12 86.12 PVP K30 Binder 40.0 40.0STEARIC ACID Lubricant 16.0 16.0 TOTAL 800.00 800.00

Process

Option 1:

1. The ingredients are weighed using a suitable balance.

2. The 4-aminosalicylate Sodium, Avicel, and Lactose are placed into asuitable granulator (e.g., high shear mixer-Diosna/Fielder).

3. Mix until a homogeneous blend is produced).

4. The PVP is dissolved in water and slowly add to the powder blend.

5. Once all the binder solution has been added to the powder blend,mixing is continued until a suitable granulation as been achieved.

6. The granules are dried in a fluidized drying machine or tray drieruntil a suitable dryness is achieved.

7. The dry granulate is then milled.

8. The dry granulate is placed in a suitable blender (V or Y typeblender), and the lubricant is added and mixed for 5 minutes.

9. The mixture is compressed into tablets (800 mg weight) on a suitabletablet machine.

Option 2:

Alternatively, 50% of the Lactose and Avicel can be used in Step 2 ofthe process. Once the dry granulate is produced, the remaining 50% ofthe Lactose and Avicel can be added to the mixer, mixed for 10 minutes.Then proceed to step 9 of the process.

Option 3:

In another alternative, the Active, Lactose, Avicel, and the PVP can bedry granulated, i.e., compressed into a dry granulator using a rollercompactor. The roller compacted material can then be passed through asuitable screen to produce granules. These granules can then be mixedwith the lubricant (i.e., Stearic acid) as in step 9 of the process.

Diffusion-Controlled Membrane Coating Formulation

Composition

Option Option Option A B C Ingredient mg/tab) mg/tab mg/tab POLYMER11.00 9.20 11.00 SUCROSE 29.00 17.00 21.00 ACETYL TRIBUTYL CITRATE 2.001.60 1.90 CASTOR OIL POLYMERISED 1.00 1.2 1.4 SODIUM HYDROGEN CARBONATE1.00 1.00 1.00 ACETONE* N/A N/A N/A TOTAL 44.00 30.00 36.30 Polymer =terpolymer of polyvinyl chloride, polyvinyl acetate and polyvinylalcohol (terpolymer PVC/PVAc/PVOH) *Solvent is removed duringprocessing.

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the desired amount of polymer coating solution has been applied,the tablets are dried on the coating machine.

Functional Coating of the Membrane-Modified Tablet

The above selectively permeable membrane tablet formulation (i.e., themembrane-modified tablet) can be additionally coated with a functionalcoat. This may be pH-dependent or pH-independent. Examples of both typesof coating are given below.

pH-Dependent Coating

Composition

Qty % Ingredient FUNCTION (w/w) EUDRAGIT L 100 Polymer 6.39 ACETYLTRIBUTYL CITRATE Plasticizer 1.60 WATER* Solvent 3.26 ETHANOL* Solvent88.75 TOTAL 100.00

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

pH-Independent Coating System

Two types of pH-independent polymer systems are described for use incoating the tablets described above.

Composition—Polymer System A

(Batch Ingredient FUNCTION g) ETHOCEL Controlled 760.00 Release PolymerMETHOCEL Controlled 330.0 Release Polymer ACETYL Plasticizer 220.00TRIBUTYL CITRATE ETHANOL Solvent 2680 WATER Solvent 451 TOTAL 4441

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

Composition—Polymer System B

(Batch Ingredient FUNCTION g) EUDRAGIT RS 12.5 Controlled 900.00 ReleasePolymer EUDRAGIT RL 12.5 Controlled 300.00 Release Polymer TALC Antadherent 105.00 DIBUTYL Plasticizer 15.00 SEBECATE MAGNESIUMAntiadherant 30.00 STEARATE ACETONE Solvent 825.00 ISOPROPYL Solvent 825ALCOHOL TOTAL 3000.0

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

Example 5 Modified Release Formulations of Disodium4,4′-Azo-Bis-Salicylate Using Methocel Premium at Various Levels (WetGranulation Method)

The 4,4′-azo-bis-salicylate is formulated in a matrix tablet to achievethe following target dissolution profiles.

Target Dissolution Profiles

Matrix Tablet without functional coating.

Time (Hours) pH 6.8 % Buffer Released 1 20 2 35 3 55 4 60 6 72 12 100

Matrix Tablet with functional coating (pH-independent Type A).

Time (Hours) pH 6.8 % Buffer Released 1 0 2 22 3 30 4 55 6 68 12 95

Matrix Tablet with functional coating (pH-independent Type B).

Time (Hours) pH 6.8 % Buffer Released 1 0 2 0 3 14 4 22 6 41 12 76

Matrix Tablet with functional coating (pH-dependent).

Time % (Hours) Released Acid 1 0 2 0 pH 6.8 Buffer 1 12 2 27 4 63 6 91

Matrix Tablet Formulation

The uncoated Matrix Tablet Formulation and processing details are givenbelow.

Composition

Ingredient FUNCTION Mg/tab Mg/tab Mg/tab Azo-bis-4- Active 571.76 571.76571.76 aminosalicylate Sodium LACTOSE Diluent 78.12 28.12 12.12 AVICELPH101 Binder 78.12 28.12 12.12 diluent METHOCEL Controlled 200.00 300.00400.00 *PREMIUM CR Release Polymer COLLOIDAL Glidant 2.00 2.00 2.00SILICON DIOXIDE STEARIC ACID Lubricant 20.0 20.00 20.0 PVP Binder 50.050.0 50.0 *ISOPROPYL Solvent N/A N/A N/A ALCOHOL TOTAL (mg) N/A 10001000 1068

Methocel grade can be changed or alternatively can be a suitablecontrolled-release polymer from the example list.

Process—Wet Granulation Process (Using Formulation Above)

1. The ingredients are weighed.

2. The Active, 50% of the Avicel, and 50% of the Lactose are placed in asuitable mixer. (For example, Planetary (Hobart), High Shear(Diosna/Fielder)).

3. The ingredients are mixed for 15 minutes to produce a homogeneousmixture.

4. Mixing is continued, while adding to the mixture the granulatingfluid (Sodium/PVP Solution).

5. The ingredients are mixed until a suitable granulation end-point isachieved (add more IPA if needed to produce a suitable granule).

6. The granules are dried (using an oven or fluidization equipment)until an acceptable level of moisture (<about 1%) and IPA (<about 0.5%)is achieved.

7. The dry granulate is passed through suitable comminution equipment(for example, Co-Mill or Fitzpatrick mill) fitted with a suitable sizedscreen (100-500 micron).

8. The granulate is placed in a blender, and colloidal Silicon Dioxideand the remainder of the Lactose and Avicel are added.

9. The mixture is blended for 15 minutes.

10. The Stearic Acid is added and mixed for 5 more minutes.

11. The mixture is compressed into tablets (target weight 1000 mg) on asuitable tablet machine.

Alternatively, the disodium 4,4′-azo-bis-salicylate can be dissolved inthe IPA (or alternative solvent), and the PVP can be mixed in the dryblend (prior to granulation).

Functional Coating of the Matrix Tablet

The above-described matrix tablet formulation can be coated with afunctional coat. This may be pH-dependent or pH-independent. Examples ofboth types of coating are given below.

pH-Independent Coating

Two types of pH-independent polymer systems are described, for use incoating the matrix tablets described above.

Composition—Polymer System A

(Batch Ingredient FUNCTION g) ETHOCEL Controlled 760.00 Release PolymerMETHOCEL Controlled 330.0 Release Polymer ACETYL Plasticizer 220.00TRIBUTYL CITRATE ETHANOL Solvent 2680 WATER Solvent 451 TOTAL 4441

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. When the required amount of polymer coating solution has beenapplied, the tablets are dried on the coating machine.

Composition—Polymer System B

(Batch Ingredient FUNCTION g) EUDRAGIT RS 12.5 Controlled 900.00 ReleasePolymer EUDRAGIT RL 12.5 Controlled 300.00 Release Polymer TALCAntiadherent 105.00 DIBUTYL Plasticizer 15.00 SEBECATE MAGNESIUMAntiadherant 30.00 STEARATE ACETONE Solvent 825.00 ISOPROPYL Solvent 825ALCOHOL TOTAL 3000.00

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried in the coating machine.

Composition—pH-Dependent Coating

Qty % Batch 1 Ingredient FUNCTION (w/w) mg/tab EUDRAGIT L 100 Polymer6.39 6.00 ACETYL TRIBUTYL Plasticizer 1.60 1.50 CITRATE WATER* Solvent3.26 N/A ETHANOL* Solvent 88.75 N/A TOTAL 100.00

Process

1. The tablets are loaded into a suitable coating machine (e.g., Glatt,Acelacota).

2. The Polymer coating solution is sprayed onto the tablets.

3. Once the required amount of polymer coating solution has beenapplied, the tablets are dried in a coating machine.

Example 6 Disodium 4,4′-Azo-Bis-Salicylate Formulations

Disodium 4,4′-azo-bis-salicylate is also incorporated into the followingformulations

Instant Release Tablet Formulations:

1. Instant-release tablet formulation without functional coat.

2. Instant-release tablet formulation with functional coat—pH-dependent.

3. Instant-release tablet formulation with functionalcoat—pH-independent.

Multiparticulate Formulations

1. Instant-release multiparticulate formulation (without functionalcoat).

2. Delayed-release multiparticulate formulation with functionalcoat—pH-dependent.

3. Delayed-release multiparticulate formulation with functionalcoat—pH-independent.

4. Controlled-release multiparticulate formulation.

5. Delayed release/modified release multiparticulate formulation.

Instant Release Tablet Formulation without Functional Coat:

An instant release tablet formulation and manufacturing process isdescribed below.

Composition (Immediate Release Tablet Formulation)

Qty % Ingredient FUNCTION (w/w) 4ASA-4ASA AZO Active 571.76 SODIUM SALTLACTOSE Diluent 128.12 AVICEL PH101 Dry Binder/ 128.12 diluent SODIIUMSTARCH Disintegrant 100.00 GLYCOLATE (EXPLOTAB) COLLOIDAL Glidant 2.0SILICON DIOXIDE STEARIC ACID Lubricant 20.00 PVP Binder 50.00 *ISOPROPYLSolvent N/A ALCOHOL TOTAL 1000 *Removed during processing.

Wet Granulation Process (Using Formulation Above)

1. The ingredients are weighed.

2. The PVP is dissolved in the IPA.

3. The 4-ASA-4ASA azo sodium salt, 50% of the Avicel, and 50% of theLactose are combined in a suitable mixer. (Planetary (Hobart), HighShear (Diosna/Fielder)).

4. The ingredients are mixed for 15 minutes to produce a homogeneousmixture.

5. Mixing is continued and the granulating fluid (PVP Solution) is addedto the mixture.

6. Mixing is continued until a suitable granulation end point isachieved (add more IPA if needed to produce a suitable granule).

7. The granules are dried (oven or fluidization equipment) untilacceptable level of moisture (<about 1%) and IPA (<about 0.5%) isachieved.

8. The dry granulate is passed through suitable comminution equipment(Co-Mill, Fitzpatrick mill) fitted with a suitable sized screen (100-500micron).

9. The granulate is placed in a blender and colloidal silicon dioxide,Sodium Starch Glycolate, and the remainder of the Lactose and Avicel areadded.

10. The combination is mixed for 15 minutes.

11. The Stearic Acid is added and the combination is mixed for 5 moreminutes.

12. The mixture is compressed into tablets (target weight 500/1000 mg)on a suitable tablet machine.

Modified-Release Multiparticulate Formulation of Disodium4,4′-Azo-Bis-Salicylate

A. Instant-Release Drug-Loaded Multiparticulates Without Functional Coat

A multiparticulate dosage form for the instant release formulation andmanufacturing process is given below.

Composition (Immediate Release Multiparticulates)

Qty Ingredient FUNCTION (mg/g) 4ASA-4ASA AZO Active 571.76 SODIUM SALTNON PAREIL Inert carrier 228.24 SEEDS PVP Binder 50.00 TALC Antiadherent125.0 COLLOIDAL Glidant 25.00 SILICON DIOXIDE SUITABLE SOLVENT SolventN/A TOTAL 1000

1. The disodium 4,4′-azo-bis-salicylate, binder, glidant, andanti-adherent are dissolved/suspended in a suitable solvent.

2. The solution/suspension is then sprayed onto the sugar spheres usingan appropriate fluidized coating machine (e.g., Glatt).

3. Once all the solution suspension has been applied on to the nonpareilseeds, the drug-loaded instant-release multiparticulates are dried inthe fluidized coating machine.

The Instant release multiparticulates and tablets described above arecoated with a combination of different modified-release polymers toproduce a number of different types of modified-releasemultiparticulates, which are described below.

B. Modified-Release tablets and/or multiparticulate formulation ofdisodium 4,4′-azo-bis-salicylate using Polymer system A.

Composition—Polymer System A

(Batch Ingredient FUNCTION g) EUDRAGIT RS 30D Controlled 200.00 ReleasePolymer TALC Antiadherent 60.00 TRIETHYL Plasticizer 12.00 CITRATESIMETHICONE Dispersant 1.00 EMULSION WATER Solvent 392.00 TOTAL 665.00

Process

1. The drug-loaded instant-release multiparticulates or tablets areloaded into a suitable fluidized coating machine (e.g., Glatt,Acelacota).

2. The polymer coating solution is sprayed onto the drug-loadedinstant-release multiparticulates.

3. Once the required amount of polymer coating solution has beenapplied, the product is dried in the fluidized coating machine.

4. For multiparticulate products, load the coated multiparticulates in ahard gelatin capsule using an automated encapsulation machine,sufficient to obtain a 250-mg dose of disodium 4,4′-azo-bis-salicylateper capsule.

An instant-release tablet can be coated with this system, resulting inan instant release tablet formulation with functional coat—pHindependent, resulting in a delayed release tablet. Also, aninstant-release multiparticulate can be coated with this system,resulting in a delayed release multiparticulate formulation withfunctional coat—pH-independent.

Modified Release Tablet and/or Multiparticulate Formulation of Disodium4,4′-Azo-Bis-Salicylate Salt Using Polymer System B

Composition—Polymer System B

(Batch Ingredient FUNCTION g) EUDRAGIT RS 12.5 Controlled 900.00 ReleasePolymer EUDRAGIT RL 12.5 Controlled 300.00 Release Polymer TALCAntiadherent 105.00 DIBUTYL Plasticizer 15.00 SEBECATE STEARIC ACIDAntiadherant 30.00 ACETONE Solvent 825.00 ISOPROPYL Solvent 825 ALCOHOLTOTAL 3000.00

Manufacturing Process—Modified-Release Multiparticulate and/or TabletDisodium 4,4′-Azo-Bis-Salicylate Formulation

Process

1. The drug-loaded instant-release multiparticulates and/or tablets areloaded into a suitable fluidized coating machine (e.g., Glatt).

2. The Polymer coating solution is sprayed onto the drug-loadedinstant-release multiparticulates and/or tablets.

3. Once the required amount of polymer coating solution has beenapplied, the product is dried in the fluidized coating machine.

4. If multiparticulate, the product is encapsulated in a hard gelatincapsule using an automated encapsulation machine, sufficient to obtain a250-mg dose of disodium 4,4′-azo-bis-salicylate per capsule.

When prepared in this manner, this represents a controlled-releasemultiparticulate formulation.

Modified Release Tablet and/or Multiparticulate Formulation of Disodium4,4′-Azo-Bis-Salicylate Using Polymer Solution C

Composition—Polymer C Formulation (pH-Dependent)

Qty % Batch 1 Ingredient FUNCTION (w/w) mg/tab EUDRAGIT L 100 Polymer6.39 6.00 ACETYL TRIBUTYL Plasticizer 1.60 1.50 CITRATE WATER* Solvent3.26 N/A ETHANOL* Solvent 88.75 N/A TOTAL 100.00

Process

1. The instant-release tablets or multiparticulates are loaded into asuitable coating machine (e.g., Glatt or Acelacota).

2. The Polymer coating solution is sprayed onto the tablets ormultiparticulates.

3. Once the required amount of polymer coating solution has beenapplied, the product is dried in the coating machine.

When prepared in this manner, this represents a delayed-releasemultiparticulate formulation with functional coat—pH dependent, or adelayed release tablet formulation with functional coat—pH dependent.

Delayed Release/Modified Release Multiparticulate Formulation

The final formulation option is a delayed-release/modified-releasetablet and/or multiparticulate formulation. This is produced by coatingthe instant-release multiparticulates and/or tablets with the Polymer Aformulation, followed by coating with either the pH-independent PolymerB formulation or the pH-dependent Polymer C formulation.

Example 7 Biostudy

An open-label, single-dose, four-treatment, four period, balanced,randomized, crossover study is designed to compare and assess therelative bioavailability of three modified-release formulations with animmediate-release reference form. Modified-release formulations areprepared as follows: a) membrane-modified formulation of 4-ASA with TypeA functional coating (see Example 3), b) membrane-modified formulationof 4-ASA with Type B functional coating (see Example 3), and c)5,5-azo-bis-salicylic acid formulated in a membrane-modified formulation(see Example 3, Type A coating).

Sixteen healthy volunteers are dosed on each of four occasions with atleast a seven-day washout period between each dose. The volunteers arefasting from food and beverages other than water for at least 4 hoursbefore dosing in each treatment period. Water is proscribed for one hourbefore and one hour after dosing except for the 150 mL of water at thetime of dosing. Venous blood samples are obtained at regular timeintervals immediately prior to and following each dosing for a period ofup to 48 hours. In addition, urine is collected over the 48-hourpost-dosing period. Concentrations of 4-ASA and n-acetylated 4-ASA(N-Ac-4-ASA) in plasma and urine are measured by HPLC using an isocraticsystem and UV detection at 300 nm. Individual plasma concentrationcurves are constructed and individual, mean, and relativepharmacokinetic parameters are estimated including Tmax, Cmax and AUC.Total urinary recovery of 4-ASA and the n-acetylated 4-ASA metaboliteare estimated.

Example 8 Treatment of Ulcerative Colitis and Crohns Disease withModified-Release 4-ASA

Modified-release formulations according to Example 3 are prepared. Asubject is diagnosed with mild to moderate ulcerative colitis or Crohn'sDisease. The subject receives a daily administration of either 4 gramsper day 4-ASA, or a pharmaceutically acceptable salt thereof, in amodified-release form. Alternatively, the subject can be given 2 gramsper day of 4,4′-azo-bis salicylic acid. Subjects are treated for 12weeks. Subjects keep daily diaries and record the number and nature ofbowel movements. The effect of the treatments is assessed by gradingclinical symptoms of fecal blood, mucus, and urgency. In addition,sigmoidoscopic assessment and biopsies are performed, and efficacy oftreatment assessed, based on grading of sigmoidoscopic and degree ofhistological inflammation in rectal biopsy specimens. Safety is assessedbased on spontaneous side effect reporting.

The formulations of this example demonstrate efficacy in both ulcerativecolitis and Crohn's Disease in terms of both treating the condition andmaintaining remission from disease symptoms.

1-18. (canceled)
 19. A pharmaceutical composition comprising: asalicylate and/or salicylic acid chosen from 5-amino salicylic acid,pharmaceutically acceptable salts and esters thereof, and pro-drugsthereof; at least one pharmaceutically acceptable excipient; and apolymer system chosen from (a) at least one of methyl cellulose andhydroxypropylmethylcellulose in combination with ethyl cellulose, and(b) at least two ammonio methacrylate co-polymers; wherein thecomposition is formulated as a modified-release pharmaceuticalcomposition with a modified-release matrix core, wherein the compositionexhibits a drug-release profile that is independent of surrounding pHand wherein the composition exhibits the following dissolution profile,when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50rpm, in pH 6.8 buffer for the test: 1 hour: less than or equal to about10% drug released; 2 hours: from about 0 to about 35% drug released; 3hours: from about 10 to about 60% drug released; 4 hours: from about 20to about 60% drug released; 6 hours: from about 40 to about 80% drugreleased; and 12 hours: from about 75 to about 100% drug released. 20.The pharmaceutical composition according to claim 19, wherein thecomposition exhibits the following dissolution profile, when tested in aU.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8buffer for the test: 1 hour: less than or equal to about 5% drugreleased; 2 hours: from about 0 to about 25% drug released; 3 hours:from about 15 to about 30% drug released; 4 hours: from about 40 toabout 50% drug released; 6 hours: from about 60 to about 75% drugreleased; and 12 hours: from about 90 to about 100% drug released. 21.The composition according to claim 19, wherein the salicylate and/orsalicylic acid is chosen from 5-amino salicylic acid andpharmaceutically acceptable salts of 5-amino salicylic acid.
 22. Thecomposition according to claim 19, wherein the salicylate and/orsalicylic acid is chosen from 5,5′-azo-bis salicylic acid andpharmaceutically acceptable salts thereof.
 23. The composition accordingto claim 19, wherein the polymer system compriseshydroxypropylmethylcellulose and ethylcellulose.
 24. The compositionaccording to claim 23, wherein the at least one pharmaceuticallyacceptable excipient comprises hydroxypropylmethylcellulose.
 25. Thecomposition according to claim 19, wherein the polymer system comprisesat least two ammonio methacrylate co-polymers.
 26. The compositionaccording to claim 19, wherein the polymer system comprises a functionalcoating and a sealant.
 27. The composition according to claim 19,wherein the functional coating comprises ethylcellulose and the sealantcomprises hydroxypropylmethylcellulose.